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Musso was born in Garland, Texas, the son of Katherine (née Moore) and Samuel Musso, who were involved in community theater in Dallas, Texas.[4] He is of Italian and English ancestry. He has two siblings – Mason Musso, who sang lead vocals in the band Metro Station with Miley Cyrus' brother Trace, and Marc Musso, an actor.[5][6]

In 2003, Mitchel made his Hollywood film debut in Secondhand Lions, alongside his brother Marc. Before Musso was cast in Secondhand Lions, he had been in several films beforehand: Am I Cursed? as Richie and The Keyman as a cub scout both in 2002. Musso also starred in three episodes of King of the Hill as the voice of Bobby Hill's friend Curt in the episodes "The Powder Puff Boys" and "Bobby Rae" as well as the surfer kid in "Four Wave Intersection" in 2007.

In early 2009, Musso was cast, alongside The Suite Life on Deck and House of Payne's Doc Shaw, in a new television series for Disney XD titled Pair of Kings. The series began production in March 2010, following the production of the final season of Hannah Montana in which Musso does not star in this season he will only be a guest. The series premiered on September 10, 2010. It was announced that Musso would be the host of Disney Channel's latest hidden camera reality series, PrankStars, which premiered on July 15, 2011.

On December 12, 2011, Disney XD renewed the series Pair of Kings for a third season. Musso did not return for the new season and, instead, he was replaced by a new character played by Adam Hicks.[7] He will remain as the voice of Jeremy Johnson on Phineas and Ferb. He also got new role in 2013 in the movie Sins Of Our Youth.

In July and August 2009, Musso opened for Metro Station. He also launched a headlining tour in August, with KSM, as his opening act. The tour concluded September 24 in New Orleans, Louisiana. On Saturday, September 4, 2010 he put on a free concert at the Great New York State Fair's Chevy Court.[9] One week later he put on another free show at the Utah State Fair. Musso's second release, "Brainstorm" was released on November 23, 2010.[10] He made a video for each one of his songs on the album to "Tell the whole story." His song Celebrate was in the radio Disney Top 3.[11]

On October 17, 2011 at 3:43 in the morning, Musso was pulled over, failed to slow down for traffic cops, and charged with a DUI suspicion. He was approached by the police who then smelled alcohol and proceeded to give him a field sobriety test and breathalyzer. Musso blew above the legal limit of .08. His bail was set at $5,000, but he was released on account of no outstanding warrants.[12] Musso told E! Online, that, "In becoming an adult, I have learned first hand that stepping up and taking responsibility is the best way to move forward. I am especially thankful to my family and fans for their unwavering support and encouragement. I am glad to now put this in the past."[13] The incident caused his character to be written out of Pair of Kings and PrankStars to be cancelled.[citation needed]